Azithromycin, a broad spectrum antibiotic derived from erythromycin A, is the generic name for 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A. It was independently discovered by Bright, U.S. Pat. No. 4,474,768 and Kobrehel, U.S. Pat. No. 4,517,359, where it was referred to by the name of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A. Bright and Kobrehel disclosed azithromycin as a hygroscopic monohydrate form. Allen, U.S. Pat. No. 6,268,489, discloses a non-hygroscopic dihydrate form of azithromycin. Both the monohydrate form and the dihydrate form are effective in treating bacterial infections when administered systemically.
The presence of food in the GI tract can significantly influence the bioavailability of an orally administered drug. If the bioavailability of a drug is affected due to the presence of food in the GI tract, the drug is said to exhibit a “food effect”. It has been reported that certain orally administered formulations of azithromycin may exhibit a food effect when administered following the ingestion of a meal. Curatolo, U.S. Pat. No. 5,605,889, discloses that orally administered capsule dosage forms of azithromycin exhibit a food effect but that tablet dosage forms, because they disintegrate rapidly following ingestion, do not exhibit a food effect. The azithromycin tablets, which do not exhibit a food effect, may contain a polymeric film coating that is soluble in the stomach, to provide ease of swallowing and an elegant appearance.
Pfizer Inc., the manufacturer of Zithromax® brand of azithromycin capsules and tablets, presented data in a 1995 Biopharmaceutics Review submitted to the Food and Drug Administration (FDA) in association with New Drug Application (NDA) 50,711 that established that the food effect of orally administered azithromycin is dependent on formulation. The data established that azithromycin orally administered in the form of a capsule exhibited a food effect but that azithromycin administered in the form of a tablet exhibited no food effect.
The data establishing a lack of food effect of azithromycin tablets in both the Curatolo, U.S. Pat. No. 5,605,889 and in association with NDA 50,711 was obtained following administration of a dosage of 500 mg (2×250 mg tablets) to each subject. The 500 mg azithromycin dosage was administered according to FDA protocol as a crossover study in which the azithromycin was administered to subjects on a first occasion either following an overnight fast or following a standard meal high in fat content. After a fifteen day washout period, the subjects were administered the azithromycin under the alternate treatment conditions. Under these conditions, it was established that the bioavailability of azithromycin administered as two 250-mg tablets was not significantly changed by a high fat diet and further established that the 250 mg tablet may be administered without restrictions relative to the ingestion of meals.
No studies have been reported concerning the presence or absence of a food effect associated with azithromycin tablets containing an amount of azithromycin less than 250 mg.
Curatolo, U.S. Pat. No. 7,108,865, discloses that orally administered azithromycin produces a dose-related incidence of gastrointestinal side effects. Side effects including diarrhea/loose stools, abdominal pain, nausea, and vomiting were reported with administration of a single dose of 1000 mg of azithromycin and also with 1500 mg of azithromycin administered over a 5 day course of azithromycin therapy consisting of 500 mg on day 1, followed by 250 mg on each of days 2 through 5. Curatolo further discloses a controlled release dosage form that decreases the exposure of the duodenum to high doses of azithromycin permits the administration of high doses of azithromycin, such as between 1 and 7 grams, with reduced incidence of side effects.
Curatolo, U.S. Pat. No. 7,108,865, does not disclose an isolated dosage of azithromycin of less than 750 mg and discloses the administration of azithromycin tablets of 250 mg only as a sequence of administrations in order to obtain a total dosage of at least 1 gram. Curatolo does not pertain to the oral administration of azithromycin at dosages below that which cause gastrointestinal side effects.
Appel, et al, WO 2006/067576, discloses a multiparticulate azithromycin tablet. The azithromycin tablet contains a multiplicity of “cores”, each of which contains azithromycin and each of which is coated with an enteric coating. The coated multiparticulates are assembled into a tablet that, upon oral administration, rapidly disintegrates to allow the coated multiparticulates to be dispersed. In this way, the object of the patent, to obtain an enterically coated multiparticulate controlled release azithromycin dosage form that decreases, relative to currently available immediate release dosage forms that deliver an equivalent dose, the incidence and/or severity of GI side effects.
Appel does not pertain to oral dosage forms of azithromycin that contain an amount of azithromycin below that which causes gastrointestinal side effects.
Regarding capsule oral dosage forms, both Curatolo, U.S. Pat. No. 5,605,889, and the 1995 Biopharmaceutics Review submitted to the Food and Drug Administration (FDA) in association with New Drug Application (NDA) 50,711 disclose a food effect. However, such food effect in capsules was established with capsules containing 250 mg of azithromycin. The presence of food effect with capsules was not studied with lower amounts of azithromycin.